"What makes this discovery significant is that we've found mutations that directly affect cancer development," says Victor Velculescu, M.D., Ph.D., senior author of the study and assistant professor at the Johns Hopkins Kimmel Cancer Center. "Most gene discoveries today focus on finding increased or decreased activity of a gene that may not affect cancer progression, akin to passengers on a bus that can't control the bus' speed or direction. What we've found are the brakes of the bus."
After analyzing 157 colon cancers, the research team found 77 mutations in six genes that make tyrosine phosphatases, enzymes that help coordinate signals that manage cellular growth, death, differentiation, and nearby tissue invasion. They normally work by turning off tumor growth, as so-called tumor suppressors, but in cancers these genes are mutated and no longer work properly. Because it is difficult to restore a mutated suppressor gene with cancer drugs, the investigators believe phosphatases themselves are not good drug targets. Yet, for every tyrosine phosphatase there is a matching enzyme, called a tyrosine kinase, which plays an opposite role, turning a pathway on and accelerating cellular events.
"If a bus' brakes are broken and they can't be fixed, another way to slow it down is to let up on the accelerator," explains Velculescu. "In this case, the faulty brakes are mutated tyrosine phosphatases and the accelerators are the tyrosine kinases." Tyrosine kinases have been of critical value in the success of such cancer-fighting drugs as Gleevec, Iressa and Herceptin, which block proteins made by tyrosine kinase genes.
Last May, Velculescu's team systematically analyzed tyrosine kinases and found mutations in this family of genes linked to more than 30 percent of colon cancer. "We will be conducting additional research to explore tyrosine phosphatase pathways and match them up with corresponding kinases in order to find targets for potential inhibitory drugs," says Zhenghe Wang, Ph.D., postdoctoral fellow and first author of the paper.
More than two-thirds of colon cancers have mutations in the tyrosine kinase and phosphatase families, as well as another kinase gene Velculescu's group identified recently. Tyrosine phosphatase mutations were also found in two of 11 (18 percent) lung cancers, two of 12 (17 percent) gastric cancers, and one of 11 (9 percent) breast cancers.
Colon cancer strikes 147,500 Americans every year and 57,100 will die from the disease.
This research was funded by the Ludwig Trust, the Maryland Cigarette Restitution Fund, the Benjamin Baker Scholarship Fund, the Clayton Fund, and the National Institutes of Health.
In addition to Velculescu and Wang, the following scientists participated in this research: Dong Shen, D. Williams Parsons, Alberto Bardelli, Jason Sager, Steve Szabo, Janine Ptak, Natalie Silliman, Brock A. Peters, Michiel S. van der Heijden, Giovanni Parmigiani, Tian-Li Wang, Greg Riggins, Kenneth W. Kinzler, and Bert Vogelstein from the Johns Hopkins Kimmel Cancer Center and Howard Hughes Medical Institute; Hai Yan, from Duke University Medical Center; Steven Powell, from UVA Health System; and James K.V. Willson and Sanford Markowitz from the Howard Hughes Medical Institute, Ireland Cancer Center, and University Hospitals of Cleveland and Case Western Reserve University.
Wang, Zhenghe, et al, "Mutational Analysis of the Tyrosine Phosphatome in Colorectal Cancers," Science, May 21, 2004.
Johns Hopkins Kimmel Cancer Center: www.hopkinskimmelcancercenter.org